The theme of our program continues to be the integration of basic laboratory studies, animal model evaluation, and clinical trials to develop improved treatment for childhood solid tumors. The program is tightly focused on new and innovative approaches to improving cytotoxic therapy, and integrating signaling inhibitors with cytotoxic therapies. The theme of the program, developmental therapeutics for solid tumors, incorporates basic studies of how cellular stress (growth factor signaling hypoxia, DNA damage) impacts on drug sensitivity in solid tumors. Emphasis has been placed on the identification of pathways upstream and downstream of DNA damage that may be targets for new therapy, and on growth factor receptors that are involved in angiogenesis and in survival of cells treated with cytotoxic agents. We have structured the program to encompass objectives that can be accomplished within this cycle of support, and objectives that, realistically, could take longer to fulfill, but that may represent radically new approaches to curative therapy. Project 1 continues therapeutic studies of IGF-IR/Akt/mTOR inhibitors, and the role of IGF-IR signaling in childhood cancers. Project 2 extends studies that have demonstrated mTOR signaling regulates cellular response to DNA damage, and mutation frequency. Project 3 continues studies that demonstrate activation of the unfolded protein response (UPR) modulates cell sensitivity to cytotoxic agents, and will examine UPR activation in clinical tumors. Project 4 will elucidate how antiangiogenic agents may modulate the pharmacology of cytotoxic agents (ABC transporters) and provide new insights into clinically relevant ways to evaluate and monitor specific changes in tumor vascularity based on noninvasive assessments of changes in tumor blood flow/vasculature (through MRI and ultrasonography). These studies will allow building detailed pharmacokinetic and pharmacodynamic models that will assist in design of our clinical studies. Project 5 will continue novel Phase l/ll trials to test ideas emanating from the preclinical projects. We will continue to optimize therapy with topotecan and irinotecan, and initiate trials of irinotecan with rapamycin. Our trials will explore novel anti-angiogenic therapies, and investigate the single agent activity of small molecule or antibody therapy targeted to the IGF-I receptor alone or combined with rapamycin. Our intent remains to advance preclinical information to the design of clinical trials, and extend these to cooperative groups.